PDBsum entry 6c2c

Hydrolase

PDB id: 6c2c

Contents

Protein chains

299 a.a.

Ligands

PEG ×2

Metals

_ZN ×4

_MG ×2

Waters ×543

PDB id:

6c2c

Name:

Hydrolase

Title:

The molecular basis for the functional evolution of an organophosphate hydrolysing enzyme

Structure:

Dihydrocoumarin hydrolase, ancdhch1. Chain: a, b. Engineered: yes

Source:

Pseudomonas sp.. Organism_taxid: 306. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.60Å R-factor: 0.175 R-free: 0.204

Authors:

N.-S.Hong,C.J.Jackson,P.D.Carr,N.Tokuriki,F.Baier,G.Yang

Key ref:

G.Yang et al. (2019). Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme. Nat Chem Biol, 15, 1120-1128. PubMed id: 31636435 DOI: 10.1038/s41589-019-0386-3

Date:

08-Jan-18 Release date: 16-Jan-19

Protein chains

No UniProt id for this chain

Struc: 299 a.a.

DOI no: 10.1038/s41589-019-0386-3

Nat Chem Biol 15:1120-1128 (2019)

PubMed id: 31636435

Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.

G.Yang, D.W.Anderson, F.Baier, E.Dohmen, N.Hong, P.D.Carr, S.C.L.Kamerlin, C.J.Jackson, E.Bornberg-Bauer, N.Tokuriki.

ABSTRACT

Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical, structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH from an ancestral dihydrocoumarin hydrolase. In-depth analyses of the adaptive landscapes encompassing this evolutionary transition revealed that the mutations form a complex interaction network, defined in part by higher-order epistasis, that constrained the adaptive pathways available. By also characterizing the adaptive landscapes in terms of their functional activities towards three additional organophosphate substrates, we reveal that subtle differences in the polarity of the substrate substituents drastically alter the network of epistatic interactions. Our work suggests that the mutations function collectively to enable substrate recognition via subtle structural repositioning.